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ToxSci Advance Access originally published online on May 2, 2003
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Toxicological Sciences 74, 192-202 (2003)
Copyright © 2003 by the Society of Toxicology

SYSTEMS TOXICOLOGY

Perturbation of Maleylacetoacetic Acid Metabolism in Rats with Dichloroacetic Acid-Induced Glutathione Transferase Zeta Deficiency

Hoffman B. M. Lantum*,1, Judith Cornejo{dagger}, Robert H. Pierce{dagger} and M. W. Anders*,2

* Department of Pharmacology and Physiology and {dagger} Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642

Glutathione transferase zeta (GSTZ1-1) catalyzes the isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate, the penultimate step in the tyrosine degradation pathway. GSTZ1-1 is inactivated by dichloroacetic acid (DCA), which is used for the clinical management of congenital lactic acidosis and is a drinking-water contaminant. Metabolic changes associated with chemically induced GSTZ1-1 deficiency are poorly understood. The objective of this study was to investigate the biochemical and toxicological effects of giving 0.3–1.2 mmol DCA/kg/day for 5 days on MAA-metabolism in male Fischer rats. Urine from DCA-treated rats inhibited {delta}-aminolevulinic acid dehydratase ({delta}-ALAD) activity, which is used for the diagnosis of hereditary tyrosinemia type I. Mass spectrometric analyses of urine from rats given DCA demonstrated elevated excretion of MAA and its decarboxylation product, maleylacetone (MA); succinylacetone (SA), the reduced analogue of MA, was not detected. DCA-induced changes in MA excretion were dose-dependent and were significantly elevated after day 2 of treatment. MA excretion was reversible after discontinuation of DCA treatment and was enhanced 10-fold by the coadministration of homogentisic acid (HGA). MA was cytotoxic to hepatocytes in vitro (EC50 ~ 350 µM) but morphological changes were not observed in liver, kidney, and brain of rats given both DCA and HGA. These data indicate that DCA-induced inactivation of GSTZ1-1 leads to formation of an MAA-derived intermediate, MA, that may be a mediator and biomarker for DCA-associated toxicities.

Key Words: dichloroacetic acid; {alpha}-haloalkanoic acid; glutathione transferase zeta; maleylacetoacetic acid; maleylacetone; succinylacetone; {delta}-aminolevulinic acid dehydratase; lactic acidosis; tyrosinemia.


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